Tau Phosphorylation Patterns in the Rat Cerebral Cortex After Traumatic Brain Injury and Sodium Selenate Effects: An Epibios4rx Project 2 Study.

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser202/Thr205-immunoreactivity (AT8-ir) and pTAU-Ser199/202-ir at 2 days, and pTAU-Thr231-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

Investigating the Role of the Hypothalamus in Outcomes to Repetitive Mild Traumatic Brain Injury: Neonatal Monosodium Glutamate Does Not Exacerbate Deficits.

Repetitive mild traumatic brain injury (RmTBI) is a prevalent and costly head injury particularly among adolescents. These injuries may result in long-term consequences, especially during this critical period of development. Insomnia and sleeping difficulties are frequently reported following RmTBI and greatly impair recovery. We sought to develop an animal model of exacerbated deficits following RmTBI by disrupting the hypothalamic circadian system. To accomplish this, we conducted RmTBI on adolescent rats that had received neonatal injections of monosodium glutamate (MSG), a known hypothalamic neurotoxin. We then examined behavioral, circadian, and epigenetic changes. MSG treated rats showed lower anxiety-like behaviors and displayed poor short-term working memory. We also showed changes in the morphology of the circadian clock in the suprachiasmatic nucleus (SCN) vasoactive intestinal polypeptide (VIP) immunostaining. VIP optical density in the SCN increased with MSG but decreased with RmTBI. There were changes in the expression of the clock genes and upregulation of the orexin receptors in response to RmTBI. MSG treated rats had longer telomere lengths than controls. Finally, although both MSG and RmTBI alone produced attenuated circadian amplitudes of activity and body temperature, exacerbated deficits were not identified in animals that received MSG and RmTBI. In sum, both MSG and RmTBI can alter behavior, circadian rhythm amplitude, SCN morphology, and gene expression independently, but the effects do not appear to be additive. Specific damage in the hypothalamus and SCN should be considered when patients experience sleeping problems following RmTBI, as this may improve therapeutic strategies.

Assessment of a nutritional supplement containing resveratrol, prebiotic fiber, and omega-3 fatty acids for the prevention and treatment of mild traumatic brain injury in rats.

Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. Adolescents are particularly vulnerable and often suffer from post-injury symptomologies that may persist for months. We hypothesized that the combination of resveratrol (RES), prebiotic fiber (PBF), and omega-3 fatty acids (docosahexaenoic acid (DHA)) would be an effective therapeutic supplement for the mitigation of mTBI outcomes in the developing brain. Adolescent male and female Sprague-Dawley rats were randomly assigned to the supplement (3S) or control condition, which was followed by a mTBI or sham insult. A behavioral test battery designed to examine symptomologies commonly associated with mTBI was administered. Following the test battery, tissue was collected from the prefrontal cortex (PFC) and primary auditory cortex for Golgi-Cox analysis of spine density, and for changes in expression of 6 genes (Aqp4, Gfap, Igf1, Nfl, Sirt1, and Tau). 3S treatment altered the behavioral performance of sham animals indicating that dietary manipulations modify premorbid characteristics. 3S treatment prevented injury-related deficits in the longer-term behavior measures, medial prefrontal cortex (mPFC) spine density, and levels of Aqp4, Gfap, Igf1, Nfl, and Sirt1 expression in the PFC. Although not fully protective, treatment with the supplement significantly improved post-mTBI function and warrants further investigation.